Tumor Progression In Ovarian Cancer Research Articles

Emerging role of the endothelin axis in ovarian tumor progression

Ovarian cancer is the leading cause of gynecologic cancer-related deaths. The endothelin (ET) axis, which includes ET-1, ET-2, ET-3, and the ET receptors, ET(A)R and ET(B)R, represents a novel target in tumor treatment. ET-1 may directly contribute to tumor growth and indirectly modulate tumor-host interactions in various tumors such as prostatic, ovarian, renal, pulmonary, colorectal, cervical, breast carcinoma, Kaposi's sarcoma, brain tumors and melanoma. Extensive experimental evidence links ET(A)R overexpression with tumor progression in ovarian cancer. ET(A)R engagement can in fact activate multiple signal transduction pathways including protein kinase C, phosphati-dylinositol 3-kinase, mitogen-activated protein kinase and transactivate epidermal growth factor receptor, which play a role in ovarian tumor growth and invasion. The effects of ET(A)R signaling are wide ranging and involve both cancer cells and their surrounding stroma, including the vasculature. Upon being activated, the ET(A)R mediates multiple tumor-promoting activities, including enhanced cell proliferation, escape from apoptosis, angiogenesis, epithelial-mesenchymal transition and increased motility and invasiveness. These findings indicate that activation of ET(A)R by ET-1 is a key mechanism in the cellular signaling network promoting ovarian cancer growth and progression. The predominant role played by ET(A)R in cancer has led to the development of small molecules that antagonize the binding of ET-1 to ET(A)R. The emerging preclinical data presented here provide a rationale for the clinical evaluation of these molecules in which targeting the related signaling cascade via ET(A)R blockade may be advantageous in the treatment of advanced stage ovarian carcinoma.

Level differentials of proteolytic factors uPA, PAI-1 and human kallikreins (hK) 5,6,7,8,10,11,13 in primary ovarian carcinoma tissues and corresponding omentum metastases impact on disease outcome

Proteolytic factors of the plasminogen activation system and human tissue kallikreins hK4–15 are involved in tumor progression in ovarian cancer. 142 primary ovarian cancer patients FIGO I-IV were operated on at Dept OB&GYN, TU Munich (median follow-up 33 months). Antigen levels of uPA, PAI-1 and 7 tissue kallikreins (hK5,6,7,8,10,11,13) were determined in primary carcinoma and corresponding omentum metastasis and related to total protein content. Level in metastases minus level in primary tumor tissue was defined as level differential. Significant increases in metastasis levels compared to primary tumor levels were found for uPA (148% of mean) and hK5 (84% of mean). Regarding progression-free survival (PFS), differences in uPA, hK6,7 and 10 had significant impact in all patients, including those with residual tumor. In univariate Cox models with fractionally ranked level differentials, larger differentials were associated with disease progression. Hazard ratios for the 75th percentile of these differentials compared to the median were: 1.50 for uPA (1.14–1.97); 1.66 for hk6 (1.16–2.39); 1.36 for hk7 (1.00–1.86); and 1.65 for hk10 (1.16–2.34). In the group of patients with no macroscopical residual tumor, only level differentials of hk5,7,8, and 11 had a significant impact on PFS. Larger differentials were linked to disease progression: according to univariate Cox models with fractionally ranked level differentials, hazard ratios for the 75th percentile of these differentials compared to the median were as follows: 2.18 (1.03–4.60) for hk5; 2.38 for hk7 (1.08–5.27); 2.6 for hk8 (1.15–6.01); and 2.03 for hk11 (1.02–4.05). The impact for uPA, hk6, and hk10 on disease progression in all patients may be attributable to poorer debulking results obtainable in patients with increased levels in their metastases. Our results show that serine proteases such as uPA and some of the tissue kallikreins play a clinically meaningful role in primary ovarian cancer.

Impact of proteolytic factors on surgical success and survival in ovarian cancer

5068 Background: Proteolytic factors of the plasminogen activation system and the human tissue kallikreins (hK4–15) have been implicated in tumor progression in ovarian cancer. Methods: In 142 ovarian cancer patients FIGO 1–4 operated on between 1985 and 1999 in the Dept. of OB&GYN of Munich Technical University (median follow-up 33 months), uPA, PAI-1, hK5–8,10,11,13 were measured by ELISA in primary tumor tissue extracts; 72 patients were optimally debulked. All patients received postoperative platinum-containing chemotherapy. Results: In univariate Cox models of progression free survival (PFS) including these measurements (fractionally ranked) plus age, pN, grading, ascites volume, and residual tumor, the strongest single predictor was presence of residual tumor (HR=4.37; 2.55–7.47). pN (HR=1.94; 1.12–3.38) and ascites volume (HR=2.37; 1.45–3.88) were also separately significant, but none of the others. In multivariate analysis of PFS, residual tumor (HR=4.76; 2.75–8.23) and hK11 (HR=0.30; 0.12–0.77) both entered the model, higher values of hK11 being associated with improved survival. Due to the strong impact of residual tumor on PFS, any factor influencing residual tumor, thus predicting surgical outcome could also be of considerable clinical interest. hK5 and 13 had significant impact on residual tumor. In univariate logistic regression, higher hK5 significantly predicted poor surgical outcome (OR=1.52; 1.25–16.6). In multivariate analysis, both hK5 and hK13 entered the model: Higher hK5 was strongly associated with residual tumor (OR=6.4; 1.63–25.0), whereas higher hK13 was associated with better surgical outcome (OR=0.16; 0.03–0.74). A ROC curve from this model classifies surgical success with AUC=0.65 (0.56–0.75). For OS, residual tumor (HR=8.7; 4.1–18.3) and hK10 (HR=0.21; 0.07–0.64) were significant in multivariate analysis. hK13 (HR=0.27; 0.08–0.85) was significant in univariate analysis only. Higher hK10 and hK13 are associated with better OS. Conclusions: Our results demonstrate that proteolytic factors are linked to tumor aggressiveness in ovarian cancer and have the potential to support clinical therapy decisions. Validation in independent data sets is currently being performed. No significant financial relationships to disclose.

Time to progression is dependent on the expression of the tumour suppressor PTEN in ovarian cancer patients.

Quantitative analyses of PTEN expression of ovarian cancer tissues were performed in this study. PTEN expression was investigated in terms of each patient's progression-free interval to indicate the role of PTEN in the generation of platinum refractory tumours. The study group comprised 20 ovarian cancer patients from whom fresh frozen tissues of both the primary tumour and specimens of progressive disease were available. The PTEN protein and phosphorylation of the downstream effector protein kinase B (PKB) were quantified by Western blot analyses and subsequent densitometry. Data were analyzed for individual PTEN variation with respect to the clinical course as defined by the progression-free interval. Applying the usual clinical criteria for platinum-sensitivity after progression, seven patients were considered platinum-sensitive whereas 13 patients had suffered a progression within 12 months after the chemotherapy. In 5/7 (71%) cases with prolonged time to progression, an increase in PTEN was observed. Decline of PTEN expression occurred in 9/13 (69%) patients with poor outcome. PTEN expression corresponds inversely to PKB phosphorylation in 14/20 (70%) tissues investigated. The data suggest that decreased PTEN expression accompanies the progression of ovarian cancer. Declining PTEN expression results in a shortened relapse-free interval, whereas an increase of PTEN prolongs the time to progression. However, as far as recurrence occurs, PTEN is not the only mechanism to suppress tumour progression in ovarian cancer.

Increased expression of the NME1 gene is associated with metastasis in epithelial ovarian cancer.

The genetic events involved in the development of metastases of epithelial ovarian cancer are largely unknown. One gene postulated to play a role in tumour metastasis suppression is NME1 (nm23-H1), and an inverse relationship between NME1 expression and metastatic potential has been observed for some solid tumours. In this study we have investigated the levels of mRNA expression of the 2 isoforms of the NME gene, NME1 and NME2. A maximum of 45 tumours samples from 33 patients were available for Northern blot analysis. We observed variable levels expression of NME1 and NME2 mRNA. The average level of NME1, but not NME2, mRNA expression was statistically higher in metastatic biopsies when compared with primary tumour biopsies. To examine the possible tumour suppressor gene role of NME1 in ovarian tumours, 76 patients were investigated by Southern blot analysis to determine the rate of allelic deletion. Allele loss at 5 other chromosome 17 loci (D17S5, TP53, NF1, D17S74, D17S4) was also evaluated for many of these 76 patients. Allele loss was observed in 22/30 (73%) informative patients at the NME1 locus. We also observed high rates of allele loss at the other loci evaluated. No correlations with clinical stage, histological subtype or patient survival were observed in either mRNA or DNA analyses. We have established that tumour progression in ovarian cancer is accompanied by over-expression of the NME1 gene; however, despite high rates of allele loss at the NME1 locus, the concept that NME1 may be a candidate tumour suppressor gene in ovarian cancer cannot be confirmed by this study.